Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease directed at the synovial joints. Its etiology and pathogenesis remain controversial. A performant model of RA is provided by the K/BxN mouse, which spontaneously develops a disorder with striking similarities to the human one (though with some differences as well). Disease development in this model depends on combined T and B cell reactivity to the glycolytic enzyme glucose-6-phosphate isomerase, or GPI. Sera or anti-GPI antibodies (Abs) from arthritic K/BxN mice can rapidly, robustly and repeatedly transfer arthritis into healthy recipients. This system has permitted significant progress in dissecting the end-stage effector mechanisms that culminate in K/BxN arthritis - implicating inflammatory cytokines, a limited set of cell types, both Fc receptors and the complement network, and GPI-containing immune complexes. On the basis of these findings, a pathogenetic scenario capable of accounting for the joint specificity of this model has been constructed. In this competing renewal application, three Specific Aims will be undertaken: 1. An assessment of the roles of un- or under-explored elements of the complement network in K/BxN serum-transferred arthritis. 2. An integration of the key molecular and cellular requirements for anti-GPI-induced arthritis, with a focus on neutrophil functions. 3. An exploration of the relevance of K/BxN disease mechanisms to human RA. Results from these experiments should prove important from two perspectives: First, they will provide a deeper understanding of the end-stage effector mechanisms that come into play during K/BxN arthritis. Second, they will allow a more informed assessment of the relationship between K/BxN and human arthritis.